Transplant Immunology Lab

Research Project Description

Composite tissue transplantation

Major soft-tissue and skeletal defects, including limb amputation, represent a deficit of form and function, as well as diminution of life quality for the affected individuals. However, any reconstructive measures to improve these non–life-threatening conditions must address a delicate balance of risks and benefits. As composite tissue transplant experiments are being conducted, a number of human hand transplants have been performed worldwide. These allografts have required an intense maintenance regimen of medications, subjecting the recipients to the significant morbidities of chronic, systemic immunosuppression. To address the risk/benefit ratio, our laboratory investigates novel techniques aiming for the induction of donor-specific tolerance to composite tissue allografts and for minimization of long-term immunosuppression. Specifically, rejection of the skin as the most immunogeneic component or a composite tissue allograft is addressed and targeted with cellular as well as pharmacological treatment.

Preliminary results of pre-clinical testing indicate that tolerance to the musculoskeletal portions of grafts as well as prolongation of skin graft survival can be achieved.

More specifically, cell-based strategies to induce tolerance include the utilization of regulatory cells such as dendritic cells. In collaboration with Dr. Angus Thomson, the tolerogenic properties of dendritic cells in composite tissue allotransplantation are investigated. Especially when kept immature, these unique antigen-presenting cells show distinct abilities for promoting graft acceptance. Our laboratory is focusing on the use of host dendritic cells as carriers of foreign peptide and inducers of donor-specific tolerance. We propose to utilize donor antigen-pulsed host dendritic cells, in conjunction with antilymphocyte serum and rapamycine, to induce tolerance to composite tissues allografts in an orthotopic hind-limb transplant model.

For the induction of tolerance to any composite tissue allograft bearing a skin component, mechanisms involved in skin allograft rejection are of exceptional importance. Hence, current and future research focuses on the induction of tolerance to the epidermal elements. For this purpose, we investigate the effect of a variety of compounds for immunosuppression of the skin component while avoiding or minimizing systemic immunosuppression.

The second major pace-limiting factor in composite tissue allotransplantation is the often unsatisfactory quality and velocity of nerve regeneration. Acceptable functional outcomes have been achieved in some patients after hand and face transplantation; in other cases, however, motor and even more sensory function has remained unsatisfactory. With this regard, strategies for monitoring nerve regeneration after face and hind limb transplantation have been developed and now serve as the basis to test components that may positively influence nerve regeneration.

Our research is considered translational research and particular attention is paid to the clinical situation when designing experiments. All compounds and methods applied are in clinical use or tested in clinical studies for different inflammatory diseases and considered promising for future use in clinical composite tissue allotransplantation.